Triggered Arrhythmias Research Articles

Abstract 11558: The Role of Oxidized CaMKII in Early Ischemia-Reperfusion Triggered Ventricular Arrhythmias

Introduction: Arrhythmias can complicate revascularization procedures after transmural infarctions and induce hemodynamic instability, but most cases can be adequately treated when they occur in hospital. However, arrhythmias that occur outside of hospital are potentially fatal. Arrhythmias in the early phase of reperfusion are caused by Ca 2+ overload and spontaneous diastolic release of Ca 2+ from the sarcoplasmic reticulum (SR). Indirect evidence suggests that reactive oxygen species (ROS) are important in this process by affecting the activity of key Ca 2+ handling proteins. Specifically, previous publications propose oxidation of the multifunctional Ca 2+ /calmodulin dependent protein kinase type II (CaMKII) to be a critical factor, and a potential therapeutic target. There is, however, a lack of data providing direct evidence for the importance of oxidized CaMKII (ox-CaMKII) for triggered arrhythmias in the early phase of reperfusion. Hypothesis: We hypothesized that ox-CaMKII increases diastolic SR Ca 2+ release events in the early phase of reperfusion. Methods: We evaluated the propensity for early reperfusion arrhythmias in mice resistant to oxidation of CaMKII in the heart (homozygous CaMKIIδ M281/282V mice) and wild type control mice (WT), by the use of Langendorff-perfused hearts exposed to ischemia-reperfusion, confocal line scan imaging of isolated cardiomyocytes transiently exposed to hypoxia and ischemia-like conditions, and immunoblotting. Results: Langendorff-perfused hearts from CaMKIIδ M281/282V mice showed no significant difference in ventricular arrhythmias compared to WT during the early reperfusion phase, both at baseline and during beta-adrenoceptor stimulation with isoprenaline. Immunoblotting of left ventricular tissue from perfused hearts revealed no significant differences in the abundance or phosphorylation levels of Ca 2+ -handling proteins. Ca 2+ imaging experiments without isoprenaline showed no significant difference in the incidence of spontaneous transients, Ca 2+ waves or Ca 2+ sparks between CaMKIIδ M281/282V and WT mice. Conclusions: Initial data indicate that ablation of CaMKII oxidation does not protect mouse hearts against arrhythmias in the early phase of reperfusion after ischemia.

Abstract 10163: Ca 2+ Within the Mitochondria Can Affect the Occurrence of Triggered Arrhythmias in Rats with Right Ventricular Hypertrophy

Background: Ca 2+ within the sarcoplasmic reticulum affects the propagation of intracellular Ca 2+ (Ca i ) waves, and the velocity of Ca i waves play important roles in the occurrence of triggered arrhythmias. It is still unknown, however, whether Ca 2+ within the mitochondria (Ca m ) affects the velocity of Ca i wave and the occurrence of arrhythmias in right ventricular (RV) hypertrophy. Objective: To know the roles of Ca m in the velocity of Ca i waves and the occurrence of triggered arrhythmias in rats with RV hypertrophy. Methods: Rats were subcutaneously injected with 60 mg/kg monocrotaline (MCT-rats) or solvent (Ctr-rats). Four weeks after the injection, trabeculae were dissected from the RVs. The force was measured using a silicon strain gauge, Ca m using rhod-2, Ca i using microinjected fura-2 and a CCD camera, and production of reactive oxygen species (ROS) from the slope DCF fluorescence during electrical stimulation. Ca 2+ waves and arrhythmias were induced by electrical stimulation (24°C). Results: MCT-rats showed a higher RV pressure, a larger weight ratio of RV free wall to left ventricle (RV/LV), and faster and larger Ca i waves than Ctr-rats (p<0.01). Among MCT-rats, Ru360 (10 μM), a mitochondrial calcium uniporter (MCU) inhibitor, decreased the occurrence of arrhythmias in trabeculae from rats with a higher RV pressure and a larger RV/LV (n=19). Ru360 decreased rhod-2 signal within trabeculae depending on the RV/LV (r=-0.85, p<0.01, n=10) without changes in Ca i transients, suggesting that inhibition of MCU decreases Ca m in MCT-rats with more severe RV hypertrophy. In addition, Ru360 decreased the velocity of Ca i waves depending on systolic RV pressure (r=-0.60, n=6) and the RV/LV (r=-0.64, n= 7), suggesting that inhibition of MCU decreased the velocity of Ca i waves in MCT-rats with higher RV pressure and more severe RV hypertrophy. Ru360 decreased the slope of DCF fluorescence (p<0.01, n=13). Conclusions: In the hearts with severe RV hypertrophy, inhibition of MCU can cause larger reduction of Ca m , decrease ROS production, and decrease the velocity of Ca i waves and arrhythmias. Thus, in the hearts with severe RV hypertrophy, more Ca 2+ may enter the mitochondria through the MCU, and higher Ca m may be involved in the occurrence of arrhythmias.

A mathematical model of hiPSC cardiomyocytes electromechanics.

Human induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CMs) are becoming instrumental in cardiac research, human‐based cell level cardiotoxicity tests, and developing patient‐specific care. As one of the principal functional readouts is contractility, we propose a novel electromechanical hiPSC‐CM computational model named the hiPSC‐CM‐CE. This model comprises a reparametrized version of contractile element (CE) by Rice et al., 2008, with a new passive force formulation, integrated into a hiPSC‐CM electrophysiology formalism by Paci et al. in 2020. Our simulated results were validated against in vitro data reported for hiPSC‐CMs at matching conditions from different labs. Specifically, key action potential (AP) and calcium transient (CaT) biomarkers simulated by the hiPSC‐CM‐CE model were within the experimental ranges. On the mechanical side, simulated cell shortening, contraction–relaxation kinetic indices (RT50 and RT25), and the amplitude of tension fell within the experimental intervals. Markedly, as an inter‐scale analysis, correct classification of the inotropic effects due to non‐cardiomyocytes in hiPSC‐CM tissues was predicted on account of the passive force expression introduced to the CE. Finally, the physiological inotropic effects caused by Verapamil and Bay‐K 8644 and the aftercontractions due to the early afterdepolarizations (EADs) were simulated and validated against experimental data. In the future, the presented model can be readily expanded to take in pharmacological trials and genetic mutations, such as those involved in hypertrophic cardiomyopathy, and study arrhythmia trigger mechanisms.

Targeting late ICaL to close the window to ventricular arrhythmias.

This commentary is on the paper by Angelini et al. Here, we set the original paper in the context of triggered arrhythmias, particularly early after depolarizations (EADs), emphasizing the importance of pharmacologically inhibiting late Ca2+ current to prevent EADs without affecting myocardial contractility.

Loss of Mitochondrial Ca2+ Uniporter Limits Inotropic Reserve and Provides Trigger and Substrate for Arrhythmias in Barth Syndrome Cardiomyopathy.

Barth syndrome (BTHS) is caused by mutations of the gene encoding tafazzin, which catalyzes maturation of mitochondrial cardiolipin and often manifests with systolic dysfunction during early infancy. Beyond the first months of life, BTHS cardiomyopathy typically transitions to a phenotype of diastolic dysfunction with preserved ejection fraction, blunted contractile reserve during exercise, and arrhythmic vulnerability. Previous studies traced BTHS cardiomyopathy to mitochondrial formation of reactive oxygen species (ROS). Because mitochondrial function and ROS formation are regulated by excitation-contraction coupling, integrated analysis of mechano-energetic coupling is required to delineate the pathomechanisms of BTHS cardiomyopathy. We analyzed cardiac function and structure in a mouse model with global knockdown of tafazzin (Taz-KD) compared with wild-type littermates. Respiratory chain assembly and function, ROS emission, and Ca2+ uptake were determined in isolated mitochondria. Excitation-contraction coupling was integrated with mitochondrial redox state, ROS, and Ca2+ uptake in isolated, unloaded or preloaded cardiac myocytes, and cardiac hemodynamics analyzed in vivo. Taz-KD mice develop heart failure with preserved ejection fraction (>50%) and age-dependent progression of diastolic dysfunction in the absence of fibrosis. Increased myofilament Ca2+ affinity and slowed cross-bridge cycling caused diastolic dysfunction, in part, compensated by accelerated diastolic Ca2+ decay through preactivated sarcoplasmic reticulum Ca2+-ATPase. Taz deficiency provoked heart-specific loss of mitochondrial Ca2+ uniporter protein that prevented Ca2+-induced activation of the Krebs cycle during β-adrenergic stimulation, oxidizing pyridine nucleotides and triggering arrhythmias in cardiac myocytes. In vivo, Taz-KD mice displayed prolonged QRS duration as a substrate for arrhythmias, and a lack of inotropic response to β-adrenergic stimulation. Cellular arrhythmias and QRS prolongation, but not the defective inotropic reserve, were restored by inhibiting Ca2+ export through the mitochondrial Na+/Ca2+ exchanger. All alterations occurred in the absence of excess mitochondrial ROS in vitro or in vivo. Downregulation of mitochondrial Ca2+ uniporter, increased myofilament Ca2+ affinity, and preactivated sarcoplasmic reticulum Ca2+-ATPase provoke mechano-energetic uncoupling that explains diastolic dysfunction and the lack of inotropic reserve in BTHS cardiomyopathy. Furthermore, defective mitochondrial Ca2+ uptake provides a trigger and a substrate for ventricular arrhythmias. These insights can guide the ongoing search for a cure of this orphaned disease.

Repolarization heterogeneity within the myocardial infarction border zone correlates with variability of myocyte remodeling

Abstract Background Myocardial infarction (MI) results in a regional scar, with a border zone (BZ) of surviving myocytes interspersed with fibrosis providing an anatomical substrate for re-entry. Heterogeneous repolarization within the BZ may add a functional component aggravating re-entrant arrhythmias. Purpose We studied BZ heterogeneity and developed novel methodology for high resolution mapping of local in vivo activation-repolarization intervals (ARI) within the BZ and for studying the relation to cellular action potential (AP) profiles of cells isolated from the BZ. Methods Anterior-septal myocardial infarction was induced in 5 domestic pigs by 120-minute occlusion of the left anterior descending artery followed by reperfusion (18.9±4.7% of the left ventricle). After 1-month, electro-anatomical mapping was performed. Contact mapping was used to define the BZ (bipolar voltage 0.5–1.5mV). A non-contact recording of a 64-electrode array was translated to 2048 non-contact electrograms distributed over the LV. The non-contact electrograms were processed to determine the ARIs using a custom-made algorithm, validated against monophasic action potential recordings. After 2–4 days recovery, single cardiomyocytes were enzymatically isolated from the anterior-septal BZs and remote regions. Cardiomyocytes were field stimulated at 1Hz at 37°C and cellular AP duration (APD) was optically recorded (fluorescent voltage-sensitive dye Di-8-Annepps). Results In vivo, regional ARIs tended to be longer in the BZs than remote. ARI heterogeneity, quantified as the standard deviation of ARIs in a neighborhood of 1cm radius, was increased in the BZ (anterior BZ: 3.4±1.0 ms, P=0.052, septal BZ: 3.6±1.7 ms, P=0.027 vs remote: 2.0±0.5 ms). Cellular APD was measured in large population samples (>100 cells per region in each pig) and was longer in BZ myocytes compared to the remote region. Cellular APD heterogeneity, measured as the standard deviation within cell population samples pooled by region per animal, was increased in the BZ (anterior BZ: 105.9±17.0 ms, P=0.0010; septal BZ: 98.1±20.8 ms, P=0.0127 vs remote: 73.9±8.6 ms). Cell APD correlated to in vivo ARI (R2=0.34, P=0.021) and cellular heterogeneity correlated strongly with in vivo heterogeneity (R2=0.67, P=0.002). Conclusion In the BZ of MI, in vivo regional heterogeneity adds a functional substrate for re-entry that may result from heterogeneous cellular remodeling and increased cell-cell APD variability. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): KU Leuven BOF-C1 “Blood pressure induced premature ventricular beats as triggers for ventricular arrhythmia in ischemic cardiomyopathy”

Sarcoplasmic Reticulum Calcium Release Is Required for Arrhythmogenesis in the Mouse.

Dysfunctional sarcoplasmic reticulum Ca2+ handling is commonly observed in heart failure, and thought to contribute to arrhythmogenesis through several mechanisms. Some time ago we developed a cardiomyocyte-specific inducible SERCA2 knockout mouse, which is remarkable in the degree to which major adaptations to sarcolemmal Ca2+ entry and efflux overcome the deficit in SR reuptake to permit relatively normal contractile function. Conventionally, those adaptations would also be expected to dramatically increase arrhythmia susceptibility. However, that susceptibility has never been tested, and it is possible that the very rapid repolarization of the murine action potential (AP) allows for large changes in sarcolemmal Ca2+ transport without substantially disrupting electrophysiologic stability. We investigated this hypothesis through telemetric ECG recording in the SERCA2-KO mouse, and patch-clamp electrophysiology, Ca2+ imaging, and mathematical modeling of isolated SERCA2-KO myocytes. While the SERCA2-KO animals exhibit major (and unique) electrophysiologic adaptations at both the organ and cell levels, they remain resistant to arrhythmia. A marked increase in peak L-type calcium (ICaL) current and slowed ICaL decay elicited pronounced prolongation of initial repolarization, but faster late repolarization normalizes overall AP duration. Early afterdepolarizations were seldom observed in KO animals, and those that were observed exhibited a mechanism intermediate between murine and large mammal dynamical properties. As expected, spontaneous SR Ca2+ sparks and waves were virtually absent. Together these findings suggest that intact SR Ca2+ handling is an absolute requirement for triggered arrhythmia in the mouse, and that in its absence, dramatic changes to the major inward currents can be resisted by the substantial K+ current reserve, even at end-stage disease.

Long-term prognosis of tachycardiomyopathy without underlying heart disease

Abstract Background Tachycardiomyopathy (TCM) is a reversible cause of left ventricular dysfunction, secondary to rapid and/or asynchronous, irregular myocardial contraction. Two categories of the disease have been described: arrhythmia-induced TCM (pure TCM), where the arrhythmia is the sole reason for the dysfunction, and arrhythmia-mediated TCM (impure TCM), where the arrhythmia can exacerbate or worsen heart failure (HF) or an underlying heart disease. Pure TCM has already been described as affecting almost 1 out of 10 patients admitted for acute HF-like symptoms. On the other side, acute HF leads to a chronic irreversible condition which tends to worsen over time and is burdened by a high rate of complications. Purpose The aim of our study was to compare pure TCM and de novo acute HF patients (including all forms of structural heart disease) in terms of mortality and cardiovascular (CV)-related hospitalizations. Methods Prospective, observational study enrolling all consecutive patients with a confirmed diagnosis of TCM and all patients admitted for de novo acute HF. The TCM diagnosis was suspected in all patients admitted for HF-related symptoms, an ejection fraction <50% with concomitant persistent atrial or ventricular arrhythmia, and confirmed after clinical and echocardiographic recovery. Acute HF diagnosis was made in all patients with an ejection fraction <50%, new HF-like symptoms, diagnosis of structural heart disease and no evidence of clinical or echocardiographic recovery. For each patient, all-cause death and CV-related hospitalizations were recorded. Propensity score matching was used in order to compare the two populations through sensitivity analysis. Results One-hundred-and-ten patients with TCM (61.8% males, 68±13 years old) were propensity matched with a control population of patients with HF and structural heart disease (76.6% males, 71±15 years old, 75% ischemic heart disease). After a median follow-up of 5.1 years (1st-3rd quartile 2.6–7.0 years) TCM patients showed an overall higher estimate of survival when compared to HF patients (78% vs. 58%; p=0.031; figure 1A) but a lower estimate of time free from CV-related hospitalization (31% vs. 57%, p=0.014; figure 1B). TCM patients got most often readmitted for AF-related elective procedures (60.8% of all hospitalizations), TCM recurrence (13.7%) and elective coronary angiography (5.9%). On the other hand, HF patients got readmitted for HF worsening (40.9%), cardiac or vascular surgery (22.7%) and elective coronary angiography (9.1%). Propensity-score matched analysis confirmed the results for all-cause death (81% vs. 49%; p=0.006) and CV-related hospitalizations (29% vs. 54%; p=0.007). Conclusions TCM is associated with a better survival when compared to de novo acute HF, even after propensity score adjustment. On the other hand, patients with TCM got readmitted more frequently, requiring more often elective procedures in order to control the triggering arrhythmia. Funding Acknowledgement Type of funding sources: None.

Abstract P396: Noncanonical Wnt5a Increases QT Interval And Susceptibility To Ventricular Arrhythmias

Background: Wnt signaling plays a critical role in both embryonic cardiogenesis and cardiac remodeling in adult heart disease. We have previously demonstrated that the canonical Wnt/β-catenin pathway inhibits cardiac sodium current, but it remains unclear whether the noncanonical Wnt pathway affects cardiac electrophysiology. Methods and Results: Western blot analysis of ventricular tissues from patients with heart failure (n=6) demonstrated a 2.3x fold increase (p<0.01) in the protein level of Wnt5a, a noncanonical Wnt ligand, as compared to healthy ventricular tissues (n=5). To investigate if Wnt5a affects cardiac electrophysiology, adenovirus expressing Wnt5a and mCherry (Ad-Wnt5a) or control adenovirus expressing mCherry only (Ad-mCherry) was injected into the left ventricular free wall of adult rat hearts. At 4-5 days after virus injection, surface ECG revealed increased QT interval (p<0.01) in Ad-Wn5a-injected rats (90.1±2.3 ms n=7, vs 72.3±2.0 ms in control Ad-mCherry rats n=7). In addition, ventricular tachycardia was induced by programmed electrical stimulation in 92% (11/12) Ad-Wnt5a hearts, but only in 22% (2/9) control Ad-mCherry hearts (p<0.01). Patch-clamp recording of isolated single ventricular myocytes demonstrated that Ad-Wnt5a myocytes exhibited marked prolongation of action potential duration (APD 90 : 273±77ms, n=5) as compared to control cells (42±12 ms, n=7, p<0.05). In addition, the prolonged action potentials in Ad-Wnt5a myocytes were associated with frequent early afterdepolarizations and delayed afterdepolarizations, two mechanisms for triggered ventricular arrhythmias. Conclusion: Wnt5a is increased in the myocardium of patients with heart failure. Viral expression of Wnt5a in rat ventricular tissue increases QT interval and ventricular arrhythmia susceptibility, which is associated with prolongation of action potentials in cardiomyocytes. This may be an important target for future therapies.

Acute Genetic Ablation of Cardiac Sodium/Calcium Exchange in Adult Mice: Implications for Cardiomyocyte Calcium Regulation, Cardioprotection, and Arrhythmia.

BackgroundSodium‐calcium (Ca2+) exchanger isoform 1 (NCX1) is the dominant Ca2+ efflux mechanism in cardiomyocytes and is critical to maintaining Ca2+ homeostasis during excitation‐contraction coupling. NCX1 activity has been implicated in the pathogenesis of cardiovascular diseases, but a lack of specific NCX1 blockers complicates experimental interpretation. Our aim was to develop a tamoxifen‐inducible NCX1 knockout (KO) mouse to investigate compensatory adaptations of acute ablation of NCX1 on excitation‐contraction coupling and intracellular Ca2+ regulation, and to examine whether acute KO of NCX1 confers resistance to triggered arrhythmia and ischemia/reperfusion injury.Methods and ResultsWe used the α‐myosin heavy chain promoter (Myh6)‐MerCreMer promoter to create a tamoxifen‐inducible cardiac‐specific NCX1 KO mouse. Within 1 week of tamoxifen injection, NCX1 protein expression and current were dramatically reduced. Diastolic Ca2+ increased despite adaptive reductions in Ca2+ current and action potential duration and compensatory increases in excitation‐contraction coupling gain, sarcoplasmic reticulum Ca2+ ATPase 2 and plasma membrane Ca2+ ATPase. As these adaptations progressed over 4 weeks, diastolic Ca2+ normalized and SR Ca2+ load increased. Left ventricular function remained normal, but mild fibrosis and hypertrophy developed. Transcriptomics revealed modification of cardiovascular‐related gene networks including cell growth and fibrosis. NCX1 KO reduced spontaneous action potentials triggered by delayed afterdepolarizations and reduced scar size in response to ischemia/reperfusion.ConclusionsTamoxifen‐inducible NCX1 KO mice adapt to acute genetic ablation of NCX1 by reducing Ca2+ influx, increasing alternative Ca2+ efflux pathways, and increasing excitation‐contraction coupling gain to maintain contractility at the cost of mild Ca2+‐activated hypertrophy and fibrosis and decreased survival. Nevertheless, KO myocytes are protected against spontaneous action potentials and ischemia/reperfusion injury.

Advanced cardiac imaging in athlete's heart: unravelling the grey zone between physiologic adaptation and pathology.

Over the last decades, interest toward athlete’s heart has progressively increased, leading to improve the knowledge on exercise-induced heart modifications. Sport may act as a trigger for life-threatening arrhythmias in patients with structural or electrical abnormalities, hence requiring to improve the diagnostic capability to differentiate physiological from pathological remodeling. Pathological alterations are often subtle at the initial stages; therefore, the challenge is to promptly identify athletes at risk of sudden cardiac death during the pre-participation screening protocols. Advanced imaging modalities such as coronary computed tomography angiography (CCTA) and cardiac magnetic resonance (CMR) can non-invasively depict coronary vessels and provide a deep morpho-functional and structural characterization of the myocardium, in order to rule out pathological life threatening alterations, which may overlap with athletes’ heart remodeling. The purpose of the present narrative review is to provide an overview of most frequent diagnostic challenges, defining the boundaries between athlete's heart remodeling and pathological structural alteration with a focus on the role and importance of CCTA and CMR.

The cardiac autonomic nervous system: an introduction

In recent decades, numerous anatomical and physiological studies of the cardiac autonomic nervous system (ANS) have investigated the complex relationships between the brain and the heart. Autonomic activation not only alters heart rate, conduction, and hemodynamics, but also cellular and subcellular properties of individual myocytes. Moreover, the cardiac ANS plays an essential role in cardiac arrhythmogenesis. There is mounting evidence that neural modulation either by ablation or stimulation can effectively control awide spectrum of cardiac arrhythmias. This article discusses anatomic aspects of the cardiac ANS, focusing on how autonomic activities influence cardiac electrophysiology. Specific autonomic triggers of various cardiac arrhythmias, in particular atrial fibrillation (AF) and ventricular arrhythmias, are also briefly discussed. Studies with heart-rate variability analysis indicate that, rather than being triggered by either vagal or sympathetic activity, the onset of AF can be associated with simultaneous discharge of both limbs, leading to an imbalance between these two arms of the cardiac ANS. At the same time, sudden cardiac death resulting from ventricular arrhythmias continues to be asignificant health and societal burden. These nerve activities of the cardiac ANS can be targeted for the treatment for cardiac arrhythmias, in particular AF and ventricular tachyarrhythmias.

PDE5 Inhibition Suppresses Ventricular Arrhythmias by Reducing SR Ca2+ Content.

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Multiphoton Imaging of Ca2+ Instability in Acute Myocardial Slices from a RyR2R2474S Murine Model of Catecholaminergic Polymorphic Ventricular Tachycardia.

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a familial stress-induced arrhythmia syndrome, mostly caused by mutations in Ryanodine receptor 2 (RyR2), the sarcoplasmic reticulum (SR) Ca2+ release channel in cardiomyocytes. Pathogenetic mutations lead to gain of function in the channel, causing arrhythmias by promoting diastolic spontaneous Ca2+ release (SCR) from the SR and delayed afterdepolarizations. While the study of Ca2+ dynamics in single cells from murine CPVT models has increased our understanding of the disease pathogenesis, questions remain on the mechanisms triggering the lethal arrhythmias at tissue level. Here, we combined subcellular analysis of Ca2+ signals in isolated cardiomyocytes and in acute thick ventricular slices of RyR2R2474S knock-in mice, electrically paced at different rates (1–5 Hz), to identify arrhythmogenic Ca2+ dynamics, from the sub- to the multicellular perspective. In both models, RyR2R2474S cardiomyocytes had increased propensity to develop SCR upon adrenergic stimulation, which manifested, in the slices, with Ca2+ alternans and synchronous Ca2+ release events in neighboring cardiomyocytes. Analysis of Ca2+ dynamics in multiple cells in the tissue suggests that SCRs beget SCRs in contiguous cells, overcoming the protective electrotonic myocardial coupling, and potentially generating arrhythmia triggering foci. We suggest that intercellular interactions may underscore arrhythmic propensity in CPVT hearts with ‘leaky’ RyR2.

Impact of pulmonary valve replacement on ventricular arrhythmias in patients with tetralogy of Fallot

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): INSERM - French Society of Cardiology OnBehalf DAIT4F Investigators Background Sudden cardiac death is a major cause of death in tetralogy of Fallot (TOF) and right ventricular overload is commonly considered as a potential trigger for ventricular arrhythmias. Purpose We aimed to assess the impact of pulmonary valve replacement (PVR) on ventricular arrhythmias burden using a population of TOF patients with continuous cardiac monitoring by implantable cardioverter defibrillator (ICD). Methods Nationwide French registry including all TOF patients with an ICD. Survival data with recurrent events were used to compare the burden of appropriate ICD therapies before and after PVR in patients who underwent PVR over the study period. Results A total of 165 patients (mean age 42.2 ± 13.3 years, 70.1% males) were included from 40 centers. Over a median (IQR) follow-up period of 6.8 (2.5-11.4) years, 26 (15.8%) patients underwent PVR. Among those patients, 18 (69.2%) experienced at least one appropriate ICD therapy. When considering all ICD therapies delivered before (n = 62) and after (n = 16) PVR, the burden of ICD appropriate therapies was significantly lower after PVR (HR 0.21, 95%CI 0.08-0.56, p = 0.002). In the overall cohort, PVR before ICD implantation was also independently associated with a lower risk of appropriate ICD therapy in primary prevention patients (HR 0.29, 95%CI 0.10-0.89, p = 0.031). Conclusions In this cohort of high-risk TOF patients implanted with an ICD, the burden of appropriate ICD therapies was significantly reduced after PVR. While optimal indications and timing for PVR are debated, these findings suggest the importance of considering ventricular arrhythmias in the overall making-decision process. Abstract Figure.

Simulated heterogeneity in purkinje-ventricular electrophysiology following acute myocardial infarction remodelling

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Wellcome Trust Senior Research Fellowship in Basic Biomedical Sciences Background Coronary heart disease is a common substrate for sudden cardiac death. Several clinical and experimental studies on ischemic heart diseases have highlighted the involvement of the His-Purkinje system in the initiation and maintenance of ventricular arrhythmias. Biophysically-detailed mathematical models and computational multiscale simulations can help in gather insights of the cellular and tissue mechanisms underlying the trigger and maintenance of arrhythmias. Purpose The goal of this study is to evaluate the effects of ionic remodelling on human Purkinje and ventricular cells in the acute stage post myocardial infarction. Methods Two recently published computational models were used to represent the electrophysiology of cardiac Purkinje and ventricular cells, including transmural heterogeneity (endo, mid, epi myocytes). Cardiac ionic remodelling was observed at the border zone of the infarcted region, mostly in canine and porcine models. For both ventricular and Purkinje models, remodelling was implemented as a variation of the number of function channels, i.e., of the current conductance for Na+, Ca2+ and K+ currents. Simulations were performed for both models at different pacing frequencies (cycle length from 400 to 1000 ms) to assess a set of action potential (AP) biomarkers and AP rate-dependence at fast pacing. Early afterdepolarisation (EADs) were induced at slow pacing under hERG block. Results Figure 1 reports the results for the ventricular (A) and Purkinje (B) electrophysiology for the healthy (blue) and post-infarction (red) tissues at 1 Hz (left), at different frequencies (middle) and under 85% hERG block at 0.25 Hz (right). At 1 Hz, ionic remodelling reduced the AP depolarisation rate, abolished the AP notch and led to AP prolongation for both models. Purkinje AP showed also elevated resting membrane potentials and increased diastolic depolarisation. The mid-cardiomyocyte and Purkinje models showed a small increase in the APD- rate dependence slope. Ionic remodelling did not affect significantly the EAD dynamics in the ventricular model, apart from further delaying the AP repolarisation. In the Purkinje model, ionic remodelling led to automaticity and changed the EAD dynamics, which disappeared from the paced AP but occurred after the spontaneous AP. Conclusion In this study we investigated the effects of ionic current remodelling in ventricular and Purkinje cells following acute myocardial infarction. Results showed that remodelling at the border zone increased the heterogeneity between Purkinje and ventricular cells. A further step into the investigation of pro-arrhythmic mechanisms induced by myocardial infarction will be to perform multiscale simulations at whole organ level in 3D anatomical models of human ventricles, including the His-Purkinje system. Abstract Figure 1

Computational modeling identifies embolic stroke of undetermined source patients with potential arrhythmic substrate.

Cardiac magnetic resonance imaging (MRI) has revealed fibrosis in embolic stroke of undetermined source (ESUS) patients comparable to levels seen in atrial fibrillation (AFib). We used computational modeling to understand the absence of arrhythmia in ESUS despite the presence of putatively pro-arrhythmic fibrosis. MRI-based atrial models were reconstructed for 45 ESUS and 45 AFib patients. The fibrotic substrate's arrhythmogenic capacity in each patient was assessed computationally. Reentrant drivers were induced in 24/45 (53%) ESUS and 22/45 (49%) AFib models. Inducible models had more fibrosis (16.7 ± 5.45%) than non-inducible models (11.07 ± 3.61%; p<0.0001); however, inducible subsets of ESUS and AFib models had similar fibrosis levels (p=0.90), meaning that the intrinsic pro-arrhythmic substrate properties of fibrosis in ESUS and AFib are indistinguishable. This suggests that some ESUS patients have latent pre-clinical fibrotic substrate that could be a future source of arrhythmogenicity. Thus, our work prompts the hypothesis that ESUS patients with fibrotic atria are spared from AFib due to an absence of arrhythmia triggers.

Melatonin Treatment Does Not Modify Ectopic Activity During Ischemia and Reperfusion in Rats

Introduction Ventricular tachycardia and/or ventricular fibrillation (VT/VF), a life-threatening complication of acute myocardial ischemia are based on the interaction between a vulnerable arrhythmogenic substrate and an arrhythmic trigger. Melatonin was proposed as a potential antiarrhythmic medication and was shown to ameliorate the arrhythmogenic substrate. Also, melatonin provides a sympatholytic effect and thereby can attenuate ectopic activity, which provides the triggers for VT/VF. However, little is known about a melatonin effect on the arrhythmic triggering. In the present study, we aimed at evaluation of the melatonin effects on catecholamine synthesis in normal and ischemic myocardium and heart rhythm disturbances during an episode of ischemia and reperfusion. Methods Experiments were done in 30 control and 32 melatonin-treated (10 mg/kg, daily, for 7 days) male rats. The hearts from 10 control and 10 treated animals were taken for histochemical analysis of sympathetic fibers (glyoxylic acid-induced fluorescence). Continuous ECG recording was performed in 20 control and 22 treated anesthetized animals before and during an ischemia-reperfusion episode induced by reversible 5-min occlusion of the left anterior descending coronary artery. Tyrosine hydroxylase expression in normal and ischemic myocardial regions was assessed by Western blotting analysis in 12 control and 12 melatonin-treated animals. Results No differences in the state of sympathetic innervation (density and fluorescence intensity) were observed in histochemical analysis. However, Western blotting demonstrated that melatonin treatment suppressed tyrosine hydroxylase expression in normal (p<0.05 vs control) but not in ischemic regions of myocardium. Melatonin-treated animals had longer RR-intervals in the baseline state, but this difference progressively disappeared during the period of ischemia due to tachycardic response to ischemia in the treated group (Figure). No differences in the number of extrasystoles were found between the control and treated groups during ischemia and reperfusion periods (Figure). Conclusion Chronic melatonin treatment led to the peripheral sympatholytic effect in myocardium, which was associated with decreased heart rate in preischemic conditions. However, this effect attenuated during ischemia and no differences in heart rate or extrasystolic burden were found between the control and treated animals during ischemia and reperfusion.

Sports Activity and Arrhythmic Risk in Cardiomyopathies and Channelopathies: A Critical Review of European Guidelines on Sports Cardiology in Patients with Cardiovascular Diseases.

The prediction and prevention of sudden cardiac death is the philosopher’s stone of clinical cardiac electrophysiology. Sports can act as triggers of fatal arrhythmias and therefore it is essential to promptly frame the athlete at risk and to carefully evaluate the suitability for both competitive and recreational sports activity. A history of syncope or palpitations, the presence of premature ventricular complexes or more complex arrhythmias, a reduced left ventricular systolic function, or the presence of known or familiar heart disease should prompt a thorough evaluation with second level examinations. In this regard, cardiac magnetic resonance and electrophysiological study play important roles in the diagnostic work-up. The role of genetics is increasing both in cardiomyopathies and in channelopathies, and a careful evaluation must be focused on genotype positive/phenotype negative subjects. In addition to being a trigger for fatal arrhythmias in certain cardiomyopathies, sports also play a role in the progression of the disease itself, especially in the case arrhythmogenic right ventricular cardiomyopathy. In this paper, we review the latest European guidelines on sport cardiology in patients with cardiovascular diseases, focusing on arrhythmic risk stratification and the management of cardiomyopathies and channelopathies.

Obstructive Sleep Apnea Syndrome as a Trigger of Cardiac Arrhythmias.

Obstructive sleep apnea syndrome (OSAS) has a high prevalence in western countries. Many papers have been published with the purpose of demonstrating that OSAS acts as an arrhythmia trigger and is responsible for an increase in cardiovascular morbidity and mortality. The aim of this study was to review our knowledge on this topic. There is a lot of evidence demonstrating the relationship between OSAS and arrhythmias, but there remains a lack of an interventional randomized trial to demonstrate that by treating OSAS we can reduce arrhythmia burden. OSAS is a highly prevalent illness in western countries and is clearly related to an increase in cardiovascular mortality and morbidity. Cardiac arrhythmias are triggered by a repetitive hypoxemia, hypercapnia, acidosis, intrathoracic pressure fluctuations, reoxygenation, and arousals during apnea and hypopnea episodes. Early diagnosis and treatment of these patients can reduce further cardiovascular morbidity and mortality.